The Effects of Tiopronin on 3-Aminopropanal Level & Neurologic Outcome After Aneurysmal Subarachnoid Hemorrhage

Summary

The purpose of this phase II study is to further assess the safety of tiopronin in aneurysmal subarachnoid hemorrhage(aSAH) patients in order to obtain preliminary data on the efficacy of tiopronin versus placebo in reducing serum and cerebrospinal fluid (CSF) 3AP levels in this patient population. Funding Source - FDA Office of Orphan Products Development

Timeline

Start

2010-04

Primary completion

2012-07

Completion

2013-07

Publications

• Background Linn FH, Rinkel GJ, Algra A, van Gijn J. Incidence of subarachnoid hemorrhage: role of region, year, and rate of computed tomography: a meta-analysis. Stroke. 1996 Apr;27(4):625-9. doi: 10.1161/01.str.27.4.625.
• Background Hop JW, Rinkel GJ, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke. 1997 Mar;28(3):660-4. doi: 10.1161/01.str.28.3.660.
• Background Mayer S, Kreiter K. Quality of life after subarachnoid hemorrhage. J Neurosurg. 2002 Sep;97(3):741-2; author reply 742. doi: 10.3171/jns.2002.97.3.0741. No abstract available.
• Background Kassell NF, Sasaki T, Colohan AR, Nazar G. Cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Stroke. 1985 Jul-Aug;16(4):562-72. doi: 10.1161/01.str.16.4.562.
• Background Solenski NJ, Haley EC Jr, Kassell NF, Kongable G, Germanson T, Truskowski L, Torner JC. Medical complications of aneurysmal subarachnoid hemorrhage: a report of the multicenter, cooperative aneurysm study. Participants of the Multicenter Cooperative Aneurysm Study. Crit Care Med. 1995 Jun;23(6):1007-17. doi: 10.1097/00003246-199506000-00004.
• Background Shohami E, Nates JL, Glantz L, Trembovler V, Shapira Y, Bachrach U. Changes in brain polyamine levels following head injury. Exp Neurol. 1992 Aug;117(2):189-95. doi: 10.1016/0014-4886(92)90126-b.
• Background Ivanova S, Botchkina GI, Al-Abed Y, Meistrell M 3rd, Batliwalla F, Dubinsky JM, Iadecola C, Wang H, Gregersen PK, Eaton JW, Tracey KJ. Cerebral ischemia enhances polyamine oxidation: identification of enzymatically formed 3-aminopropanal as an endogenous mediator of neuronal and glial cell death. J Exp Med. 1998 Jul 20;188(2):327-40. doi: 10.1084/jem.188.2.327.
• Background Dogan A, Rao AM, Hatcher J, Rao VL, Baskaya MK, Dempsey RJ. Effects of MDL 72527, a specific inhibitor of polyamine oxidase, on brain edema, ischemic injury volume, and tissue polyamine levels in rats after temporary middle cerebral artery occlusion. J Neurochem. 1999 Feb;72(2):765-70. doi: 10.1046/j.1471-4159.1999.0720765.x.
• Background Seiler N. Polyamine oxidase, properties and functions. Prog Brain Res. 1995;106:333-44. doi: 10.1016/s0079-6123(08)61229-7.
• Background Ivanova S, Batliwalla F, Mocco J, Kiss S, Huang J, Mack W, Coon A, Eaton JW, Al-Abed Y, Gregersen PK, Shohami E, Connolly ES Jr, Tracey KJ. Neuroprotection in cerebral ischemia by neutralization of 3-aminopropanal. Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5579-84. doi: 10.1073/pnas.082609299. Epub 2002 Apr 9.
• Background Cockroft KM, Meistrell M 3rd, Zimmerman GA, Risucci D, Bloom O, Cerami A, Tracey KJ. Cerebroprotective effects of aminoguanidine in a rodent model of stroke. Stroke. 1996 Aug;27(8):1393-8. doi: 10.1161/01.str.27.8.1393.
• Background Wood PL, Khan MA, Moskal JR. Neurochemical analysis of amino acids, polyamines and carboxylic acids: GC-MS quantitation of tBDMS derivatives using ammonia positive chemical ionization. J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Feb 2;831(1-2):313-9. doi: 10.1016/j.jchromb.2005.12.031. Epub 2006 Jan 10.
• Background Wood PL, Khan MA, Moskal JR, Todd KG, Tanay VA, Baker G. Aldehyde load in ischemia-reperfusion brain injury: neuroprotection by neutralization of reactive aldehydes with phenelzine. Brain Res. 2006 Nov 29;1122(1):184-90. doi: 10.1016/j.brainres.2006.09.003. Epub 2006 Oct 5.
• Background Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery. 1980 Jan;6(1):1-9. doi: 10.1227/00006123-198001000-00001.
• Background Lindell A, Denneberg T, Hellgren E, Jeppsson JO, Tiselius HG. Clinical course and cystine stone formation during tiopronin treatment. Urol Res. 1995;23(2):111-7. doi: 10.1007/BF00307941.
• Ironside N, Christophe B, Bruce S, Carpenter AM, Robison T, Yoh N, Cremers S, Landry D, Frey HP, Chen CJ, Hoh BL, Kim LJ, Claassen J, Connolly ES. A phase II randomized controlled trial of tiopronin for aneurysmal subarachnoid hemorrhage. J Neurosurg. 2019 Jul 12;133(2):351-359. doi: 10.3171/2019.4.JNS19478. Print 2020 Aug 1.

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